Evaluating heterogeneity in cumulative meta-analyses

BACKGROUND: Recently developed measures such as I(2 )and H allow the evaluation of the impact of heterogeneity in conventional meta-analyses. There has been no examination of the development of heterogeneity in the context of a cumulative meta-analysis. METHODS: Cumulative meta-analyses of five smoking cessation interventions (clonidine, nicotine replacement therapy using gum and patch, physician advice and acupuncture) were used to calculate I(2 )and H. These values were plotted by year of publication, control event rate and sample size to trace the development of heterogeneity over these covariates. RESULTS: The cumulative evaluation of heterogeneity varied according to the measure of heterogeneity used and the basis of cumulation. Plots produced from the calculations revealed areas of heterogeneity useful in the consideration of potential sources for further study. CONCLUSION: The examination of heterogeneity in conjunction with summary effect estimates in a cumulative meta-analysis offered valuable insight into the evolution of variation. Such information is not available in the context of conventional meta-analysis and has the potential to lead to the development of a richer picture of the effectiveness of interventions

Deconstructing the DGAT1 enzyme: membrane interactions at substrate binding sites

Diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in the triacylglyceride synthesis pathway. Bovine DGAT1 is an endoplasmic reticulum membrane-bound protein associated with the regulation of fat content in milk and meat. The aim of this study was to evaluate the interaction of DGAT1 peptides corresponding to putative substrate binding sites with different types of model membranes. Whilst these peptides are predicted to be located in an extramembranous loop of the membrane-bound protein, their hydrophobic substrates are membrane-bound molecules. In this study, peptides corresponding to the binding sites of the two substrates involved in the reaction were examined in the presence of model membranes in order to probe potential interactions between them that might influence the subsequent binding of the substrates. Whilst the conformation of one of the peptides changed upon binding several types of micelles regardless of their surface charge, suggesting binding to hydrophobic domains, the other peptide bound strongly to negatively-charged model membranes. This binding was accompanied by a change in conformation, and produced leakage of the liposome-entrapped dye calcein. The different hydrophobic and electrostatic interactions observed suggest the peptides may be involved in the interactions of the enzyme with membrane surfaces, facilitating access of the catalytic histidine to the triacylglycerol substrates

Precision of genetic parameters and breeding values estimated in marker assisted BLUP genetic evaluation

In practical implementations of marker-assisted selection economic and logistic restrictions frequently lead to incomplete genotypic data for the animals of interest. This may result in bias and larger standard errors of the estimated parameters and, as a consequence, reduce the benefits of applying marker-assisted selection. Our study examines the impact of the following factors: phenotypic information, depth of pedigree, and missing genotypes in the application of marker-assisted selection. Stochastic simulations were conducted to generate a typical dairy cattle population. Genetic parameters and breeding values were estimated using a two-step approach. First, pre-corrected phenotypes (daughter yield deviations (DYD) for bulls, yield deviations (YD) for cows) were calculated in polygenic animal models for the entire population. These estimated phenotypes were then used in marker assisted BLUP (MA-BLUP) evaluations where only the genotyped animals and their close relatives were included

Accuracy of genomic breeding values in multi-breed dairy cattle populations

<p>Abstract</p> <p>Background</p> <p>Two key findings from genomic selection experiments are 1) the reference population used must be very large to subsequently predict accurate genomic estimated breeding values (GEBV), and 2) prediction equations derived in one breed do not predict accurate GEBV when applied to other breeds. Both findings are a problem for breeds where the number of individuals in the reference population is limited. A multi-breed reference population is a potential solution, and here we investigate the accuracies of GEBV in Holstein dairy cattle and Jersey dairy cattle when the reference population is single breed or multi-breed. The accuracies were obtained both as a function of elements of the inverse coefficient matrix and from the realised accuracies of GEBV.</p> <p>Methods</p> <p>Best linear unbiased prediction with a multi-breed genomic relationship matrix (GBLUP) and two Bayesian methods (BAYESA and BAYES_SSVS) which estimate individual SNP effects were used to predict GEBV for 400 and 77 young Holstein and Jersey bulls respectively, from a reference population of 781 and 287 Holstein and Jersey bulls, respectively. Genotypes of 39,048 SNP markers were used. Phenotypes in the reference population were de-regressed breeding values for production traits. For the GBLUP method, expected accuracies calculated from the diagonal of the inverse of coefficient matrix were compared to realised accuracies.</p> <p>Results</p> <p>When GBLUP was used, expected accuracies from a function of elements of the inverse coefficient matrix agreed reasonably well with realised accuracies calculated from the correlation between GEBV and EBV in single breed populations, but not in multi-breed populations. When the Bayesian methods were used, realised accuracies of GEBV were up to 13% higher when the multi-breed reference population was used than when a pure breed reference was used. However no consistent increase in accuracy across traits was obtained.</p> <p>Conclusion</p> <p>Predicting genomic breeding values using a genomic relationship matrix is an attractive approach to implement genomic selection as expected accuracies of GEBV can be readily derived. However in multi-breed populations, Bayesian approaches give higher accuracies for some traits. Finally, multi-breed reference populations will be a valuable resource to fine map QTL.</p

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

\ua9 2024 The AuthorsIn the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI

Conservation of the role of INNER NO OUTER in development of unitegmic ovules of the Solanaceae despite a divergence in protein function

The P-SlINO::SlINO-GFP transgene continues to be expressed after fertilization during the onset of fruit development. A-C: Ovules from P-SlINO::SlINO-GFP plants. D, E: Ovules from control plants. Images A (confocal) and B (DIC overlaid with GFP channel) show expression in the outer cell layer in an ovule post-anthesis. C-E are images of the surface cells of the integument of ovules taken from 3–4 mm fruits. C and D are images taken on an epifluorescence microscope (Axioplan) using a Chroma GFP filter set 41017 (Chroma, Bellows Falls, VT). E is a dark-field image of the same ovule in D. These images show expression is present in developing fruit. Scale bar in B represents 20 μm, scale bar in E represents 20 μm in C-E. (TIF 4435 kb

Is tension band wiring technique the "gold standard" for the treatment of olecranon fractures? A long term functional outcome study

<p>Abstract</p> <p>Background</p> <p>Tension band wiring (TBW) remains the most common operative technique for the internal fixation of olecranon fractures despite the potential occurrence of subjective complaints due to subcutaneous position of the hardware. Aim of this long term retrospective study was to evaluate the elbow function and the patient-rated outcome after TBW fixation of olecranon fractures.</p> <p>Methods</p> <p>We reviewed 62 patients (33 men and 29 women) with an average age of 48.6 years (range, 18–85 years) who underwent TBW osteosynthesis for isolated olecranon fractures. All patients were assessed both clinically with measurement of flexion-extension and pronation-supination arcs and radiologically with elbow X-Rays. Functional outcome was estimated using the Mayo Elbow Performance Score (MEPS), Visual Analogue Scale (VAS) subjective pain score and VAS patient satisfaction score. Follow up: 6–13 years (average 8.2 years).</p> <p>Results</p> <p>There was a higher prevalence of fractures among men until the 5th decade of life and among women in elderly (p = 0.032). Slip or simple fall onto the arm was the main mechanism of injury for 38 fractures (61.3%) while high energy trauma, such as fall from a height (> 2 m) or road accident, was reported in 24 fractures (38.7%). Hardware removal performed in 51 patients (82.3%) but 34 of them (66.6% of removals) were still complaining for mild pain during daily activities. The incidence of pin migration and loosening was not statistically decreased when penetration of the anterior ulnar cortex was accomplished (p = 0.304). Supination was more often affected than pronation (p = 0.027). According to MEPS, 53 patients (85.5%) had a good to excellent result, 6 (9.7%) fair and 3 (4.8%) poor result. The average satisfaction rating was 9.3 out of 10 (range, 6–10) with 31 patients (50%) to remain completely satisfied from the final result. Degenerative changes recorded in 30 elbows (48.4%). However, no correlation could be found between radiographic findings and MEPS (p = 0.073).</p> <p>Conclusion</p> <p>Tension band wiring fixation remains the "gold standard" for the treatment of displaced and minimally comminuted olecranon fractures. In long term, low levels of pain may be evident regardless of whether the metalware is removed and degenerative changes have been developed.</p

Digital karyotyping reveals probable target genes at 7q21.3 locus in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is a worldwide malignant liver tumor with high incidence in China. Subchromosomal amplifications and deletions accounted for major genomic alterations occurred in HCC. Digital karyotyping was an effective method for analyzing genome-wide chromosomal aberrations at high resolution.</p> <p>Methods</p> <p>A digital karyotyping library of HCC was constructed and 454 Genome Sequencer FLX System (Roche) was applied in large scale sequencing of the library. Digital Karyotyping Data Viewer software was used to analyze genomic amplifications and deletions. Genomic amplifications of genes detected by digital karyotyping were examined by real-time quantitative PCR. The mRNA expression level of these genes in tumorous and paired nontumorous tissues was also detected by real-time quantitative RT-PCR.</p> <p>Results</p> <p>A total of 821,252 genomic tags were obtained from the digital karyotyping library of HCC, with 529,162 tags (64%) mapped to unique loci of human genome. Multiple subchromosomal amplifications and deletions were detected through analyzing the digital karyotyping data, among which the amplification of 7q21.3 drew our special attention. Validation of genes harbored within amplicons at 7q21.3 locus revealed that genomic amplification of SGCE, PEG10, DYNC1I1 and SLC25A13 occurred in 11 (21%), 11 (21%), 11 (21%) and 23 (44%) of the 52 HCC samples respectively. Furthermore, the mRNA expression level of SGCE, PEG10 and DYNC1I1 were significantly up-regulated in tumorous liver tissues compared with corresponding nontumorous counterparts.</p> <p>Conclusions</p> <p>Our results indicated that subchromosomal region of 7q21.3 was amplified in HCC, and SGCE, PEG10 and DYNC1I1 were probable protooncogenes located within the 7q21.3 locus.</p

The use of microbubbles to target drug delivery

Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed